Abstract
Classical Chinese pharmacopeias describe numerous excellent herbal formulations, and each prescription is an outstanding pool of effective compounds for drug discovery. Clarifying the bioactivity of the combined mechanisms of the ingredients in complex traditional Chinese medicine formulas is challenging. A classical formula known as Qingfei Xiaoyan Wan, used clinically as a treatment for prevalent chronic lung disease, was investigated in this work. A mutually enhanced bioactivity-guided ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) characterization system was proposed, coupled with a dual-luciferase reporter assay for β2AR-agonist cofactor screening. Arctiin, arctigenin, descurainoside and descurainolide B, four lignin compounds that showed synergistic bronchodilation effects with ephedrine, were revealed. The synergistic mechanism of arctigenin with the β2ARagonist involved with the reduction of free Ca2+ was clarified by a dual-luciferase reporter assay for intracellular calcium and the Ca2+ indicator fluo-4/AM to monitor changes in the fluorescence. The relaxant and contractile responses of airway smooth muscle are regulated by crosstalk between the intracellular cAMP and calcium signaling pathways. Our data indicated the non-selective βAR agonist ephedrine as the principal bronchodilator of the formula, whereas the lignin ingredients served as adjuvant ingredients. A greater understanding of the mechanisms governing the control of these pathways, based on conventional wisdom, could lead to the identification of novel therapeutic targets or new agents for the treatment of asthma and COPD.
Highlights
In recent decades, biotechnology has provided novel approaches to drug development and generated new classes of biological therapeutics
Balanced salt solution (HBSS) (Ca2+ and Mg2+ free), Dulbecco’s modified Eagle medium (DMEM), and fetal bovine serum (FBS) reagents for the cell culture were purchased from HyClone (UT, USA)
The Bronchodilator Effect of Qingfei Xiaoyan Wan (QFXY) The guinea pig asthma model was established to validate the bronchodilation effect of high, middle and low doses of QFXY (397.5, 132.5, and 44.1 mg/100 g, respectively) and ephedra extract (EE) (0.146 mg/100 g)which containing the same dose of ephedrine with the middle dose QFXY
Summary
Biotechnology has provided novel approaches to drug development and generated new classes of biological therapeutics. Combinatorial medicines have been gaining acceptance in the West, and examples of these combinations include the drug cocktails used to treat acquired immunodeficiency syndrome and cancer, as well as complex antibiotic medications [7,8]. These therapeutics contain a limited number of pure compounds that have been well characterized. A number of herbal medicines and ancient TCM prescriptions are novel therapeutic regimens against COPD or asthma [18,19,20,21]; naturalb2AR agonists or antagonists participate in the regulation process, and TCM prescription compatibility enhances the regulation pathway more effectively [22]. Several ingredients that have synergistic effects with ephedrine on the b2AR/cAMP signal pathway were suggested, and the efficacies and mechanisms were tested
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